The overall objective of this project is to define the role of transforming growth factor-beta (TGF-beta as regulator of macrophage activation for tumor cell killing. The central hypothesis is that TGF-beta is an important autocrine modifier of mouse macrophage activation that is regulated, in part, by controlling the extracellular processing of this latent secreted cytokine. The following specific aims have been formulated to test this hypothesis: (1) to determine the ability of various macrophage-activating stimuli to induce the production of latent and active TGF-beta. These studies will involve close collaboration with Projects #1 and #3 and will use protocols for mouse macrophage activation developed by Drs. Morrison, Russell and Pace. A significant portion of these studies will be devoted to understanding how latent TGF-beta becomes activated by macrophages; (2) to define in detail the effects of TGF-beta has on macrophage responses that lead to different mechanisms of tumor cell killing. The activation pathway leading to macrophage tumoricidal activity are diverse and may vary considerably in their susceptibility to the effects of TGF-beta. Other projects in this program have defined pathways by which macrophages are activated or their effector functions are regulated. The effects of TGF-beta on a variety of these LPS and IFN induction pathways and killing mechanisms will be characterized as a means of better understanding the interplay between TGF-beta and other macrophage-inducing stimuli; and (3) to identify those regulator effects of TGF-beta that are expressed in an autocrine fashion. These studies will not only determine whether macrophages produce, activate and respond to TGF-beta in an autocrine fashion, but will determine by what mechanisms this autocrine regulation is expressed. Overall, these studies should elucidate the mechanism by which mouse macrophages regulate the production of active TGF-beta and how, once activated, this cytokine affects the induction of cytolytic potential in macrophages. The importance of these studies lie in their value in understanding macrophage biology and the intricacies of regulatory processes that lead to tumor cell killing by this cell type. The results may suggest ways in which the biological effects of TGF-beta could be exploited to enhance the destruction of tumor cells in vivo.